Percutaneous transluminal angioplasty (PTA) has attained significant success in the treatment of discrete atherosclerotic lesions in the coronary and non-coronary vasculature. This procedure involves percutaneously introducing a specially constructed catheter equipped with a balloon on the distal shaft into the vasculature, guiding the catheter system to an area of vascular stenosis and inflating the balloon to effect a dilatation of the stenotic area. The techniques of PTA, well known in the arts of interventional cardiology and interventional radiology, provides effective alternatives to the more invasive surgical methods of vascular reconstruction and bypass. More recently, PTA has been complemented by other endovascular procedures that allow diagnosis and treatment of vascular lesions. Examples of these endovascular procedures include atherectomy, intraluminal stenting and grafting, thromboembolectomy, angioscopy and endovascular ultrasonography. Major endovascular methods for treating a vascular stenosis include balloon dilatation, debulking or excising plaque, and providing an intraluminal scaffold or stent.
A comprehensive mechanism for a successful angioplasty has been proposed whereby the atherosclerotic intima is ruptured and partially dehisced, thereby freeing the media from the adherent restraint of the atherosclerotic plaque and allowing the media to become overstretched. (WR Castenada-Zuniga et al.: The mechanism of balloon angioplasty, Radiology 135:565-571, 1980) The overstretching distends the media and results in some injury to its elastic elements and muscle fibers. Blood flow in the lumen keeps the media distended as it heals by collagen deposition. The vessel thus reforms in its new configuration, resulting in a permanent widening of the vessel lumen. Balloon angioplasty results in extensive injury to all layers of the vessel wall, including plaque fracture, media stretch, dissection and rupture, and adventitial stretch with focal ruptures in adventitial collagen. Healing of these lesions takes place at all levels, requiring full-thickness repair of the arterial wall. Postulated repair mechanisms within the media and the adventitial include sequences of inflammation, neovascularization, fibroblast proliferation and eventual collagen deposition.
Much research interest has focused on the changes that occur in the intimal layer following angioplasty. The intima is generally considered to consist of a single layer of endothelial cells and a thin basal lamina. Successful PTA involves interruption of the intimal layer of the vessel, thus violating the impermeable barrier that the intima provides between the blood flowing within the vessel lumen and the deeper layers of the vessel itself. Endovascular surgery can induce similar trauma. Under normal conditions, the healthy intima allows for smooth blood flow within the vascular channel and minimizes the risk of triggering intravascular thrombosis. In its normal state, the smooth layer of endothelial cells comprising the intima is actively antithrombotic. Vessels with altered endothelial coverage are at increased risk for intravascular thrombosis. Restoration of intimal integrity is therefore a paramount concern for unimpeded blood flow.
Early complications of PTA reflect the acute, full-thickness injury to the vessel wall that the procedure entails. These complications, including plaque dissection and thrombosis, can result in an abrupt closure of the vessel that has undergone PTA. Early reocclusion of a recanalized vessel is commonly due to thrombus formation, a process set in motion by the vascular injury associated with the endoluminal manipulation. Endothelial injury associated with PTA triggers the coagulation cascade which results in thrombin production. Thrombin, in turn, has many related actions, including the production of fibrin and the activation of platelets. Fibrin and platelets join together within the vessel to form a thrombus. The thrombus then obstructs the blood vessel partially or completely. Abrupt closure of a vessel causes acute ischemia in the perfused tissues. In the coronary circulation, abrupt closure can cause myocardial infarction or death if blood flow is not emergently restored.
The later onset of vessel occlusion following endovascular intervention is termed restenosis. Restenosis can occur following any endovascular treatment of a stenotic condition. Restenosis has been well-studied following PTA. Approximately one-third of PTA patients require a second or third therapeutic intervention due to restenosis. The etiology of this condition following PTA involves mechanisms of vascular healing following the trauma induced by this procedure.
The intima damaged by endovascular procedures heals by re-endothelialization and neointimal formation. Intimal repair, however, involves not only the endothelial cells but also the cells of the media. One striking characteristic of the normal healthy vessel wall is the slow growth rate of both the intimal endothelial cells and the smooth muscle cells (SMCs) of the media. Damage to the vascular endothelium is understood to trigger a complex series of events by which these cells undergo a transformation from their normal resting state to a state of heightened biological activity.
In response to vessel wall injury, SMCs undergo a series of distinct changes, the earliest of which is replication. This is followed by migration from the media across the internal elastic lamina into the intima. Once in the intima, the SMCs proliferate and ultimately synthesize and secrete extracellular matrix. This cellular proliferation, as well as the deposition of connective tissue elements, forms the basis of the observed intimal changes in the lumen of a traumatized vessel. Some investigators prefer to call these phenomena myointimal hyperplasia rather than intimal hyperplasia to underscore the role of the medial smooth muscle cell.
The biological complexity of these acute and longer-term events has inspired investigators to consider pharmacological means for their manipulation in order to preserve the beneficial effects of endovascular procedures. For example, regulation of SMC hyperplasia may affect rates of restenosis. Since SMCs are understood to dedifferentiate from a contractile to a synthetic phenotype, followed by intense proliferation and the production of connective tissue, one method of combating restenosis might be the administration of various therapeutic agents known to block these processes. Additional therapeutic interventions could modulate the inflammatory processes or the thrombotic processes, both of which have been implicated in abrupt occlusion or restenosis.
Delivering the therapeutic agents to these target tissues poses problems, however. Systemically administered drugs such as anticoagulants, vasodilators, etc., have proven ineffective in preventing restenosis. Furthermore, conventional methods of systemic drug delivery produce blood levels that may have dangerous side-effects. Finally, there is an inevitable fluctuation of serum drug concentrations following systemic administration, providing inconstant levels of the active agent available to the target tissues.
Local intramural therapy may also be applied to non-arterial luminal structures including the prostate via the prostatic urethra, the fallopian tubes, the ureters and the gastrointestinal tract. Local administration of therapeutic agents to vascular tissues following PTA and related endovascular procedures has been proposed using a variety of systems. General problems with local administration include difficulties with retaining the agent in the vicinity of the lesion and risks of further injuring the vessel wall following endovascular trauma. A successful device must both provide adequate concentration of therapeutic agent to the treatment area and must also avoid further trauma to the already damaged vessel wall. No such device yet exists in the art.
Several devices have been disclosed which place the treatment apparatus containing the therapeutic agent in contact with the vessel wall at the site to be treated and simply release the agent onto the vessel wall. (See U.S. Pat. No. 5,087,244, issued to Wolinsky et al., U.S. Pat. No. 5,242,158, issued to Arney, U.S. Pat. No. 5,389,314, issued to Wang, and U.S. Pat. No. 5,213,576, issued to Abiuso et al.) With these systems, the agent is placed in contact with the treatment area but is mostly washed away by the bloodstream, resulting in unnecessary distal dissemination, inadequate local perfusion or both. Further, the infusion process can create a forceful stream of fluid exiting from the treatment apparatus that directly impinges upon the vessel wall. If high pressure is used during inflation, the fluid may be forced through the perforations in an infusion balloon at a high velocity, with resultant damage to the local tissue. This contact, termed "jetting" can extend the zone of injury produced by the PTA. Examples of the damage that can result from jetting include direct cellular injury, edema formation and vessel wall rupture. The vascular damage due to jetting can exacerbate the processes that lead to the development of intimal hyperplasia and ultimately result in restenosis.
Other devices exist that propose a direct application or injection of the drug to a segment of the vessel wall so that the drug penetrates into the deeper layers. U.S. Pat. No. 5,112,305, issued to Barath et al., teaches a method of treatment of an atherosclerotic blood vessel that delivers a therapeutic agent to the blood vessel wall through a rapid bolus of a therapeutic agent into tubular extensions of the balloon. This system, though, can produce increased damage to an already traumatized area with uncontrolled risk of endothelial and medial injury. Further, there is an imprecise application of the therapeutic agent, with risk of its loss downstream. U.S. Pat. No. 5,354,279, issued to Hofling, discloses a system of needle injectors that penetrate the vessel wall for direct application of a therapeutic agent within the wall. However, there is no calibration system to determine the depth of the needles, and the injectors themselves may further traumatize the wall of the moving vessel. U.S. Pat. No. 5,693,029, issued to Leonhardt, discloses a catheter system designed to overcome the rigidity of the Hofling catheter and to puncture the vessel wall to a controlled depth, but does not avoid mechanical wall trauma. U.S. Pat. No. 5,611,775, issued to Machold, discloses a catheter with multiple apertures designed to inject fluid into the tissue wall under pressure, thus again possibly producing further vessel wall injury.
There therefore remains in the art an unmet need for a system that provides controlled local delivery of a therapeutic agent to the vessel wall but that avoids the dangers of extending the local injury resulting from endovascular procedures. The availability of a drug delivery system that achieves these two goals would permit more successful manipulation of the biological environment within the blood vessel wall. Intervening in the biological processes of vessel wall healing can in turn reduce the incidence of restenosis following PTA and other endoluminal procedures for vascular disease, thereby resulting in more durable clinical benefits.